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Cancer Lett. 2008 Oct 18;270(1):1-9. doi: 10.1016/j.canlet.2008.03.036. Epub 2008 May 7.

Genomic instability in myeloid malignancies: increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair.

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1
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Abstract

Disease progression in myeloid malignancies results from the accumulation of "mutations" in genes that control cellular growth and differentiation. Many types of genetic alterations have been identified in myeloid diseases. However, the mechanism(s) by which these cells acquire genetic alterations or "Genomic instability", is less well understood. Increasing evidence suggests that the genetic changes in myeloid malignancies lead to increased production of endogenous sources of DNA damage, such as, reactive oxygen species (ROS). The fusion gene BCR-ABL in chronic myeloid leukemia (CML), FLT3/ITD in acute myeloid leukemia (AML), and RAS mutations in myelodysplastic syndromes (MDS)/myeloproliferative diseases (MPD) result in ROS production. Increased ROS can drive a cycle of genomic instability leading to DNA double strand breaks (DSBs) and altered repair that can lead to acquisition of genomic changes. Evidence is coming to light that defects in a main repair pathway for DSBs, non-homologous end-joining (NHEJ), lead to up-regulation of alternative or "back-up" repair that can create chromosomal deletions and translocations. This article will review evidence for activation of RAS/PI3K/STAT pathways, that lead to increased ROS, DNA damage and defective repair in myeloid diseases, a mechanism for acquisition of additional mutations that can drive disease progression.

PMID:
18467025
DOI:
10.1016/j.canlet.2008.03.036
[Indexed for MEDLINE]
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